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Asparagine endopeptidase cleaves ?-synuclein and mediates pathologic activities in Parkinson's disease.

ABSTRACT: Aggregated forms of ?-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of ?-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human ?-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human ?-synuclein at N103 in an age-dependent manner. AEP is highly activated in human brains with PD, and it fragments ?-synuclein, which is found aggregated in Lewy bodies. Overexpression of the AEP-cleaved ?-synuclein1-103 fragment in the substantia nigra induces both dopaminergic neuronal loss and movement defects in mice. In contrast, inhibition of AEP-mediated cleavage of ?-synuclein (wild type and A53T mutant) diminishes ?-synuclein's pathologic effects. Together, these findings support AEP's role as a key mediator of ?-synuclein-related etiopathological effects in PD.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC5871868 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease.

Zhang Zhentao Z   Kang Seong Su SS   Liu Xia X   Ahn Eun Hee EH   Zhang Zhaohui Z   He Li L   Iuvone P Michael PM   Duong Duc M DM   Seyfried Nicholas T NT   Benskey Matthew J MJ   Manfredsson Fredric P FP   Jin Lingjing L   Sun Yi E YE   Wang Jian-Zhi JZ   Ye Keqiang K  

Nature structural & molecular biology 20170703 8

Aggregated forms of α-synuclein play a crucial role in the pathogenesis of synucleinopathies such as Parkinson's disease (PD). However, the molecular mechanisms underlying the pathogenic effects of α-synuclein are not completely understood. Here we show that asparagine endopeptidase (AEP) cleaves human α-synuclein, triggers its aggregation and escalates its neurotoxicity, thus leading to dopaminergic neuronal loss and motor impairments in a mouse model. AEP is activated and cleaves human α-synuc  ...[more]

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